Probucol is a well-known antioxidant that is chemically related to 2-[3]-tert-butyl4-hydroxyanisole, 2,6-di-tert-butyl4-methylphenol and the like. These materials are commonly used in foods to prevent oxidative deterioration. The compound probucol, 4,4'-(isopropylidenedithio) bis(2,6-di-tert-butylphenol), is represented by the following structural formula ##STR4##
The preparation of this compound is a multistep process, starting by reacting a solution of the appropriately-substituted 4-mercaptophenol with acetone, in the presence of a catalytic amount of hydrochloric acid. Probucol precipitates from the reaction mixture and is readily separated and purified. The reaction is described in detail in U.S. Pat. No. 3,862,332 (Barhhart et al).
Similarly, probucol and certain of its derivatives is also described in U.S. Pat. No. 3,485,843 (Wang), U.S. Pat. No. 3,576,833 (Neuworth) and U.S. Pat. No. 4,985,465 (Handler).
As noted above, probucol is related to antioxidants found useful as food additives. However, this compound has also proven effective as a serum cholesterol-lowering agent for treating patients suffering from hypercholesterolemia. Further, probucol has been suggested as an effective antiviral compound (see U.S. Pat. No. 4,985,465 cited above) as well as a compound that may be active in treating arrhythmia (see U.S. Pat. No. 4,719,273 to McCaughn).
Administration of probucol itself into the human body is difficult because of its lack of solubility in aqueous solutions. While it cannot be injected intravenously and is poorly miscible in buffered solutions, solid dosage forms such as tablets or capsules are commercially available for administration. Unfortunately, even this route is subject to problems, since uptake by the body is poor. It appears that patients administered the same concentration of probucol obtain sera levels of the compound that differ by as much as 20 times. In order to avoid the low water solubility problems associated with probucol utilization in the body, water-soluble derivatives have been prepared that spontaneously hydrolyze in aqueous environments to probucol. Thus, U.S. Pat. No. 5,262,439 (Parthasarathy), incorporated herein in its entirety by reference, disclose a class of water-soluble probucol derivatives having one or more ester groups replacing the phenolic hydroxyl group of the probucol molecule. Some of the compounds disclosed in this reference have polar or charged functionalities attached to the ester group, e.g., the groups carboxylic acid, amide, amino, and aldehyde. The method for preparing these water-soluble probucol compounds involves the treatment of a solution of probucol with the carboxylic acid anhydride compound bearing the desired polar or charged functionality in the presence of a catalyst. The catalyst is disclosed to be 4-(dimethylamino)pyridine. While the reaction is relatively simple in concept, the isolation of the desired derivative is complex to the point that economically acceptable yields of these water-soluble derivatives is not possible.
Accordingly, there is a need for a method to prepare water-soluble derivatives of probucol that is simple and provides the di sired compound in good yields.